Immunoglobulin heavy chain isotype switch recombination is a regulated recombination event that occurs in antigen-activated B cells. Switch recombination joins the variable region of an expressed heavy chain gene to a constant region of a new class or isotype, deleting the DNA between. Since each of the different classes of constant region removes antigen in a specialized way, the result of switch recombination is to alter the antigen clearance properties of an immunoglobulin molecule without affecting its specificity for antigen, thereby increasing the efficiency of the immune response. The critical importance of switching is evidenced by the fact that certain immunodeficiency diseases are characterized by an inability to carry out switch recombination. The proposed research will study the molecular mechanism of isotype switch recombination. The aims are: (1) to carry out structure-function analysis of LR1, a B cell-specific switch region binding protein; (2) to determine how the subunits of LR1 interact with each other, and to ask if they also interact with specific nuclear repair/recombination proteins and with RNA; and (3) to identify a nuclease in switching B cells that specifically cleaves switch region sequences.